Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS-UMR7104, Université de Strasbourg, Illkirch-Graffenstaden, France.
Nat Commun. 2022 Jul 15;13(1):4112. doi: 10.1038/s41467-022-31566-z.
SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function.
SLITRK2 是一种单次跨膜蛋白，在突触后神经元中表达，调节轴突生长和兴奋性突触的维持。在本研究中，我们报道了通过外显子组测序在神经发育障碍个体中鉴定到的 X 染色体上 SLITRK2 的罕见变异（一个无义变异和六个错义变异）。功能研究表明，一些变体显示出膜转运受损和促进兴奋性突触的作用受损。引人注目的是，这些变化使 SLITRK2 野生型降低神经元中受体酪氨酸激酶 TrkB 水平的能力丧失。此外，Slitrk2 条件性敲除小鼠表现出长期记忆受损和步态异常，重现了 SLITRK2 变异患者的部分临床特征。此外，海马 CA1 特异性 Slitrk2 cKO 引起的兴奋性突触维持受损导致空间参考记忆异常。总的来说，这些数据表明 SLITRK2 参与了 X 连锁神经发育障碍，这是由 SLITRK2 功能的多个方面受到干扰引起的。
